Milling process for the production of finely milled medicinal substances

ABSTRACT

The present invention is a method of milling materials to form a fine powder with a median particle size below 10 micrometer which is suitable for inhalation and which has substantially no amorphous content generated during milling. The method is particularly suitable for milling materials which are soft. The method comprises milling the material in a fluid energy mill at reduced temperature using helium, or helium mixed with another gas, as milling fluid. Temperatures of −30° C. or less are used.

[0001] This application is a continuation of International ApplicationNo. PCT/GB99/04047, filed Dec. 1, 1999, incorporated herein byreference.

[0002] The present invention relates to a process for the production offinely milled medicinal substances intended for use as inhalationmedicaments.

[0003] Inhalation medicaments must have a fine particle size in order topenetrate deep into the lungs where they can be absorbed. Typicallyparticles less than 10 microns in size are required. Such fine particlesare normally prepared by milling the material to be inhaled. It is wellknown that the intensive milling required to produce these fine particlesizes can produce profound changes in the crystal structure of thematerial being milled. The exact changes are governed by the nature ofthe starting material but commonly freshly milled powders have a greatlyincreased content of amorphous phase. This initially forms on thesurface of the particles but can constitute a large proportion of thetotal weight of the powder.

[0004] Changes in crystal structure, including increase in amorphouscontent, can cause a number of problems. The particles tend to sticktogether, making the freshly milled powder extremely cohesive. Withtime, often under the influence of ambient moisture, the surface phasetends to revert to its more stable original phase. This can cause theparticles to be welded together. Furthermore, the crystal form of apharmaceutical substance can have a significant effect on its potency,as discussed by J. I. Wells in Pharmaceutical Preformulation: ThePhysiochemical Properties of Drug Substances, John Wiley & Sons, NewYork (1988). We have now found that by careful control of the millingconditions used we can achieve the required particle size for aninhalation medicament without generating amorphous phases on the surfaceof the powder.

[0005] U.S. Pat. No. 5,562,923 describes a method for producing finelymilled highly crystalline medicinal substances intended for use asinhalation medicaments by drying the milled medicament, treating with anon aqueous solvent and then drying. U.S. Pat. No. 5,637,620 uses adifferent method; the milled medicament is conditioned under controlledconditions of temperature and humidity before being dried.

[0006] In a fluid energy mill the material to be milled is entrained inan airstream and the particles caused to collide with one another byturbulence in the air stream. However, the energy input to the powdersurface tends to produce a phase change to an amorphous state. Onepossible solution to this problem would be to mill at a reducedtemperature. The material to be milled is likely to be more brittle andfriable, resulting in a lower energy input to each powder particle. Alsophase change reactions tend to proceed more slowly at lowertemperatures. To be effective temperatures well below 0° C. arerequired. One problem with this approach is that the milling fluids mostcommonly used, nitrogen and air, become less effective as theirtemperature drops. In particular the exit velocity of the gas from themilling nozzles becomes too low.

[0007] We have now found that this problem can be overcome by usinghelium as milling fluid. The process provides finely milled, highlycrystalline material containing substantially no amorphous material. Asurprising advantage is that build up of scale in the mill duringmilling is much reduced. Less scale is deposited and the scale which isdeposited is less hard and easier to remove.

[0008] Therefore, according to the present invention there is provided amethod for producing fine, highly crystalline material consisting offluid energy milling of crystalline material using a milling fluidcomprising helium at reduced temperature.

[0009] Pure helium can be used or a mixture of helium and another gas.Thus, for example, nitrogen and/or air can be mixed with helium. Purehelium is preferred. Preferably the milling temperature falls within therange of −30 to −120° C., more preferably in the range −50 to −70° C.

[0010] The milling process may be applied to any crystalline material.However it may particularly be used to mill medicament powders,especially medicament powders intended for administration by inhalation.It is particularly advantageous when applied to soft powders which aredifficult to mill to a fine uniform particle size.

[0011] The particle size of the product is controlled in theconventional manner by adjusting pressure and flow rate of the millingfluid and feed rate of the material to be milled. Any equipmentconventionally used in combination with a fluid energy mill to helpcontrol product particle size distribution can also be used inconjunction with the claimed method. The reduced tendency to form scaleis particularly advantageous when a classifier is used in conjunctionwith the mill.

[0012] We have also found that it is possible to produce extra finepowder by the method described above. Milled powders with a medianparticle size as low as 1 micron can be produced. The lower limit ofpowder median particle size which is produced by conventional fluidenergy milling is around 2 to 3 micron.

[0013] The amount of amorphous material in a sample of milled powder canbe assessed in a number of ways. Differential Scanning Calorimetry (DSC)will show the heat of crystallisation in a sample containing amorphousmaterial. Alternatively the change in weight of a sample exposed to anatmosphere of controlled temperature and humidity can give a measure ofthe change in amorphous content. In both methods the apparatus iscalibrated using samples of known crystalline content and the unknownsample measured by comparing the magnitude of the measurement for theunknown with the known samples.

[0014] Also, amorphous substances usually have a substantially higherspecific surface area than the corresponding crystalline substance.Thus, when a powder with an appreciable amorphous content crystallisesthe specific surface area falls. When a powder produced by conventionalmilling with a substantial amorphous content is stored in contact withthe atmosphere the amorphous material tends to crystallise over a periodof time. Within a few days, or weeks at most, surface area falls to asubstantially stable value.

[0015] Accordingly, in the context of the present invention a powder maybe considered to have substantially no amorphous content if its specificsurface area does not change substantially when stored in a containeropen to the atmosphere for a week or more. The change in surface areashould preferably be no more than 20% of the initial value, morepreferably no more than 10% and most preferably no more than 5%.Alternatively a powder would be considered to have substantially noamorphous content if the level immediately after milling as measured byweight change under controlled relative humidity or DSC is less than 5%,more preferably less than 2% and most preferably less than 1%.

[0016] Surface area can be measured by gas absorption using theBrunauer-Emmet-Teller method or by air permeametry using the Blainemethod. Results given here relate to the latter method which isdescribed in the standard method of the l'Association Francaise deNormalisation (AFNOR) no P 15-442 March 1987.

[0017] Weight change under controlled relative humidity is measuredusing a DVS 1 dynamic vapour sorption apparatus. A small weighed sampleis placed in a microbalance pan and held at constant temperature of 25°C. and a relative humidity of 75%. Weight change is measured as afunction of time over a period of at least 5 hours. The plot of weight vtime shows a peak which is proportional to the proportion of amorphousmaterial present. The equipment is calibrated with samples of knownamorphous content produced by mixing fully crystalline and fullyamorphous materials.

[0018] DSC measurements were carried out using a Seiko RDC 220 system.The sample is weighed into the measuring pan and held at a temperaturebelow the recrystallisation temperature for 30 minutes under a flow ofdry nitrogen to remove any surface moisture. The sample was then heatedat a constant rate of 20° C. per minute. The exothermic peak due torecrystallisation is measured. As above the method is calibrated usingsamples of known amorphous content.

EXAMPLE

[0019] A two inch diameter pancake mill was used for the experiments.Helium is introduced to the circumference of the mill and powder to bemilled is blown in through a venturi orifice also entering through thecircumference of the milling chamber. Milled product, entrained in themilling fluid, exits through a central outlet. The temperature of themilling gas and/or the feed gas can be controlled.

[0020] The table below gives results obtained when milling triamcinoloneacetonide (TAA) according to the present invention. The same feed wasused in all cases and the starting material had a median particle size(d50) as measured by Malvern particle size analyser of around 25 micron.The gas used was helium or nitrogen in all cases.

[0021] Surface area was measured using the Blaine air permeabilitymethod. Where samples were stored for ageing trials the samples werekept in a 60% relative humidity atmosphere at 25° C.

[0022] Run 1 and Run 2 compare the effects of room temperature heliumand nitrogen as milling gas. Helium gives a finer, higher surface areaproduct but both products have a relatively high amorphous content.

[0023] Run 3 used nitrogen at −7° C. as milling gas. Again a relativelyhigh amorphous content was produced.

[0024] Run 4 and Run 5 used cold helium as the milling and carrier gas.The product had no detectable amorphous content and was alsosignificantly finer than would be expected given the milling conditionsRun 1 Run 2 Run 3 Run 4 Run 5 Feeding rate (kg/h) 0.1 1 0.1 1 1 Millingpressure (bar) 4 5 7 5 5 Feed gas pressure (bar) 5 7 9 7 7 Gas HeliumNitrogen Nitrogen Helium Helium Temperature (° C.) Room T Room T −7 −65−50 mill size (inches) 2 4 2 4 4 Product Sw (m²/g) 3.2 1.5 1.2 3.0 3.3Product Sw (m²/g) after one week — — — 2.9 — Product Sw (m²/g) after twoweeks — — — — 3.3 Product d50 (μm) — — — 1.5 1.5 Amorphous content (%)7.6 3.2 5.8 n.d. n.d.

[0025] Product from Run 5 was tested in an Ultrahale® device and theresults compared with product milled in the conventional way. TheUltrahaler® is a dry powder inhaler whose basic operation is describedin EP 407 028.

[0026] A compact was produced by compressing a mixture of 5% milledproduct with 95% lactose with a median particle size of 50 micrometer.The compact is loaded into the inhaler and doses cut off from it using ablade. Up to 200 doses can be obtained from each device. The importantparameters are dose uniformity and the percentage respirable fraction ofmedicament produced in each dose.

[0027] For product produced by conventional means the mean respirablefraction produced was 44% and 83% of the doses cut were within 20% oftheir nominal weight. For product produced under the conditions of Run 5the mean respirable fraction was 40% but the percentage of doses within20% of nominal weight rose to 90%.

What is claimed is:
 1. A method for producing a fine, highly crystallinematerial product, the method comprising fluid energy milling acrystalline material using a milling fluid comprising helium at reducedtemperature.
 2. A method according to claim 1 wherein the milling fluidconsists of helium.
 3. A method according to claim 1 wherein thetemperature of the milling fluid is between −30° C. and −120° C.
 4. Amethod according to claim 3 wherein the temperature of the milling fluidis between −50° C. and −70° C.
 5. A method according to claim 1 whereinthe crystalline material comprises a medicament powder.
 6. A methodaccording to claim 5 wherein the crystalline material is triamcinoloneacetonide.
 7. A method according to claim 1 wherein the product has anamorphous content of less than 5%.
 8. A method according to claim 7wherein the product has an amorphous content of less than 2%.
 9. Amethod according to claim 8 wherein the product has an amorphous contentof less than 1%.
 10. A method according to claim 1 wherein the productcomprises a medicament powder in a form suitable for inhalation.
 11. Amethod according to claim 10 wherein the product has a median particlesize of less than 1 0 microns.
 12. A crystalline material containingsubstantially no amorphous content and having a median particle size ofless than 2 microns.
 13. A crystalline material according to claim 12having a median particle size of about 1 micron.
 14. A crystallinematerial according to claim 12 which is triamcinolone acetonide.
 15. Acrystalline material produced by a method according to claim
 1. 16. Acrystalline material according to claim 15 containing substantially noamorphous content and having a median particle size of less than 2microns.